FDA Issues Complete Response Letter for Trastuzumab Biosimilar

Citing the need for additional technical information, the FDA has issued a complete response letter to Pfizer regarding a biologics license application (BLA) for the trastuzumab (Herceptin) biosimilar PF-05280014.

Pfizer had previously reported data from the REFLECTIONS B327-02 study (N = 707) at the 2017 ESMO Congress demonstrating that PF-05280014 had achieved equivalence in objective response rate (ORR) compared with trastuzumab when the agents were combined with paclitaxel for the frontline treatment of patients with HER2-positive metastatic breast cancer (risk ratio = 0.940, achieving the equivalence margin of 0.8-1.25 specified in the trial design).

Survival rates at 1 year (56% with PF-05280017 vs 52% with trastuzumab), along with progression-free survival rates (88.84% vs 87.96%), were also comparable between the biosimilar and the reference product. REFLECTIONS B327-04, a separate trial presented at the 2017 ESMO Congress, also demonstrated clinical equivalence regarding the efficacy and safety of PF-05280014 and trastuzumab.

“The additional requested information does not relate to safety or clinical data submitted in the application. Pfizer is working closely with the FDA to address the contents of the letter and remains committed to bringing this important medicine to patients in the United States,” the company reported in a statement.

Trastuzumab has approved FDA indications for the treatment of patients with HER2-positive breast cancer, as well as HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma.

The only FDA-approved biosimilar for trastuzumab (Herceptin) is MYL-1401O (Ogivri; trastuzumab-dkst), which is co-developed by Mylan and Biocon. MYL-1401O has approved indications for HER2-positive patients with breast cancer or metastatic gastric or gastroesophageal junction adenocarcinoma, the same indications as trastuzumab. Genentech, the manufacturer of trastuzumab, holds an exclusive license for the metastatic gastric cancer indication. The companies cannot market the drug for that purpose until the exclusive license expires.

Mylan and Biocon submitted a BLA to the FDA for MYL-1401O in November 2016, and the agency had set an action deadline of September 3, 2017. In July 2017, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 16-0 to recommend approval of MYL-1401O. However, on August 30, the FDA announced that it had extended its decision deadline on the BLA by 3 months.

The BLA included phase III results from HERiTAge, a 2-part, multicenter, double-blind, randomized, parallel-group study. Patients with measurable HER2-positive metastatic breast cancer who had not received prior chemotherapy or trastuzumab for metastatic disease were randomly assigned to MYL-1401O (n = 230) or trastuzumab with docetaxel or paclitaxel (n = 228).

Patients underwent a minimum of 8 cycles in Part 1 of the trial, with trastuzumab continuing until progression. Both forms of trastuzumab were administered with a loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks.

In Part 2, patients who had stable disease or better could continue with MYL-1401O or trastuzumab. The primary endpoint was ORR. Secondary endpoints included progression-free survival, overall survival, time to progression, safety, and tolerability.

MYL-1401O demonstrated an ORR after 24 weeks of 69.6% among women who received the biosimilar in combination with a taxane compared with a 64% ORR for patients who took trastuzumab plus a taxane. The ratio of ORR for MYL-1401O to trastuzumab was 1.09—both 90% CI (0.974-1.211) and 95% CI (0.954-1.237). The difference in ORR between the 2 arms was 6.0% (90% CI, -1.3%-13.2%). At the week 48 cutoff, the median duration of response was 9.7 months in both groups.

In the per protocol population, ORR was 70% for MYL-1401O compared with 67% for trastuzumab. The ratio of ORR was 1.06 (90% CI, 0.96-1.18).

Progression-free survival was nearly identical between the 2 groups (stratified HR, 0.95; 95% CI, 0.71-1.25). Median overall survival had not been met in either group.

Safety data also were comparable. Serious adverse events (AEs) occurred in 39.3% of the patients in the MYL-1401O arm compared with 37.0% in the trastuzumab arm, with neutropenia as the most frequently reported serious AE in both arms (57.5% vs 54.1%, respectively).

The BLA also included 2 nonclinical animal studies: a single-dose comparative pharmacokinetic study in cynomolgus monkeys comparing MYL-1401O to EU-trastuzumab, and a 4-week, repeat-dose toxicity and toxicokinetic study in cynomolgus monkeys comparing MYL-14010 to EU-trastuzumab.

A BLA for another biosimilar trastuzumab candidate, SB3, was accepted for review by the FDA in December 2017, according to Samsung Bioepis, which is codeveloping the agent with Merck (MSD).